Severe Traumatic Brain Injury (TBI) is a major public health concern and is a leading cause of mortality and morbidity throughout the world (3). In addition to direct injury to the brain, TBI may lead to complications in other organs, such as the lungs. Acute Lung Injury (ALI; 2) is a common cardiopulmonary problem after trauma and is associated with a hospital mortality rate of up from 40% (4). TBI patients, in particular, are susceptible to develop ALI, with some studies reporting an incidence as high as 30% (5). Recent studies have shown that systemic inflammatory factors may lead to pulmonary dysfunction and lung injury after TBI (6), but the precise molecular mechanism underlying TBI-induced lung injury remain poorly defined.
A flood of secreted inflammatory mediators, including cytokines, chemokines, and damage-associated molecular patterns (DAMPs) released by injured cells contribute to brain inflammation and affect distal organs such as the lungs (5). One of the most widely studied DAMPs is the high mobility group box-1 (HMGB1), which can serve as an early mediator of inflammation in various pathogenic states, including TBI (7). A more recent study has shown that HMGB1 can be involved in the mechanism of TBI-induced pulmonary dysfunction (8). HMGB1 release can be regulated by the inflammasome (9), a multi-protein complex involved in the activation of caspase-1 and the processing of IL-1β and IL-18 after TBI (10).
A variety explanations have been put forth to explain pathomechanisms of pulmonary complications after TBI, including increased vascular permeability leading to capillary leakage and infiltration of proteinaceous debris (11). Extracellular vesicles (EV) are membrane-contained vesicles that play a role in cell-to-cell communication (12) and have been implicated to play a role in the development of ALI in a LPS-induced murine model. Further, it has been shown that EV can carry bioactive cytokines such as IL-1β and inflammasome proteins (13) (14), and may trigger an immune response and amplify inflammation via its cargo to neighboring and surrounding cells. However, it is unknown if EV-mediated inflammasome signaling can contribute to the pathomechanism of TBI-induced ALI. Further, it is also unknown whether the pathomechanisms of TBI-induced ALI are shared by other conditions that produce lung inflammation. In addition, there is a scarcity of Federal Drug Administration (FDA) approved drugs to treat lung inflammation.
Accordingly, there is an urgent need not only for elucidating the pathomechanisms of lung inflammation caused by TBI as well as other conditions, but also the development of therapeutic compositions and uses thereof for treating and/or preventing lung inflammation.